Self-sufficing H2O2-responsive nanocarriers through tumor-specific H2O2 production for synergistic oxidation-chemotherapy

• Published in: Journal of controlled release 2016-03, Vol.225, p.64-74
• Main Authors: Li, Junjie, Ke, Wendong, Wang, Lei, Huang, Mingming, Yin, Wei, Zhang, Ping, Chen, Qixian, Ge, Zhishen
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Agents, Phytogenic - therapeutic use; Camptothecin - administration & dosage; Camptothecin - chemistry; Camptothecin - pharmacology; Camptothecin - therapeutic use; Cell Line, Tumor; Cell Survival - drug effects; DNA Damage; Drug Carriers - administration & dosage; Drug Carriers - chemistry; Drug Carriers - pharmacology; Drug Carriers - therapeutic use; Drug Liberation; Female; H2O2 production; Hybrid micelles; Hydrogen Peroxide - metabolism; Mice, Inbred BALB C; Micelles; Nanostructures - administration & dosage; Nanostructures - chemistry; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Oxidation-chemotherapy; Oxidation-Reduction; Polymer prodrug; Polymers - administration & dosage; Polymers - chemistry; Polymers - pharmacology; Polymers - therapeutic use; Reactive oxygen species (ROS)-responsive
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2016.01.029

One of distinct features in tumor tissues is the elevated concentration of reactive oxygen species (ROS) during tumor immortality, proliferation and metastasis. However, ROS-responsive materials are rarely utilized in the field of in vivo tumoral ROS-responsive applications due to the fact that the intrinsic ROS level in the tumors could not escalate to an adequate level that the developed materials can possibly respond. Herein, palmitoyl ascorbate (PA) as a prooxidant for hydrogen peroxide (H2O2) production in tumor tissue is strategically compiled into a H2O2-responsive camptothecin (CPT) polymer prodrug micelle, which endowed the nanocarriers with self-sufficing H2O2 stimuli in tumor tissues. Molecular oncology manifests the hallmarks of tumoral physiology with deteriorating propensity in eliminating hazardous ROS. H2O2 production was demonstrated to specifically sustain in tumors, which not only induced tumor cell apoptosis by elevated oxidation stress but also served as autochthonous H2O2 resource to trigger CPT release for chemotherapy. Excess H2O2 and released CPT could penetrate into cells efficiently, which showed synergistic cytotoxicity toward cancer cells. Systemic therapeutic trial revealed potent tumor suppression of the proposed formulation via synergistic oxidation-chemotherapy. This report represents a novel nanomedicine platform combining up-regulation of tumoral H2O2 level and self-sufficing H2O2-responsive drug release to achieve novel synergistic oxidation-chemotherapy. [Display omitted]